This invention concerns a tablet adapted for controlled release of various pharmaceuticals.
It, Controlled release pharmaceutical dosage forms are commercially available. Zero order drug release from dosage forms is desired in order to provide a uniform and sustained drug delivery to a patient, but this is not easily achieved. Osmotic pump tablets are known (U.S. Pat. No. 5,545,413), and do a good job of providing zero order drug release. These tablets comprise a rigid coating membrane having an aperture formed therethrough using a laser. Gastrointestinal fluids penetrate the semipermeable coating membrane, and the core of the device generates sufficient pressure to force drug out through the laser-drilled aperture. These tablets generally provide a lag time of up to about two hours before beginning to release drug because some time is required for gastrointestinal fluids to penetrate the semipermeable coating membrane, and for the core of the device to generate sufficient pressure to begin forcing drug out through the aperture.
The osmotic pump tablets provide several advantages, including drug release which is independent of both pH and ionic strength. Moreover, drug release is not affected by erosion as a result of peristaltic gastrointestinal motion. Although these dosage forms provide zero-order drug release, they suffer from many problems in large-scale production. The semipermeable membranes which control water flow into the tablet, but block water flow out of the tablet, must be cast using organic solvents which are environmental pollutants closely regulated by the Environmental Protection Agency. This alone makes the process very expensive and undesirable. Moreover, laser equipment is required to drill the effluent hole in each tablet through which the drug must exit. Special equipment is required to position each tablet, one-at-a-time, correct side up, to drill the laser hole.
There also are problems associated with drug delivery using these osmotic pump tablets. For example, since drug can exit the tablet only through the aperture, any tablet which becomes trapped with the aperture against the gastrointestinal wall will pump drug directly into a localized spot on the mucous membrane. Thus, mucosal irritants, such as indomethacin and other non-steroidal anti-inflammatory drugs, should not be administered using osmotic pump tablets. Osmotic tablets do not release drug in some desirable ways, such as sustained fashion in the lower intestine, e.g., sustained colonic drug delivery without prior delivery of much of the drug in the upper gastrointestinal tract.
Hydrophilic-gum-matrix, controlled-release tablets are much easier to produce than osmotic pumps and provide sustained drug release. However, such tablets do not provide good zero-order drug release and cannot provide a lag time prior to drug release. These tablets do not provide pulsatile drug delivery. Further, hydrophilic gum matrix tablets undergo erosion in the gastrointestinal tract as a result of peristaltic activity such that drug release is much faster during times of high GI activity, which occurs with meals, than when the GI tract is quiescent, such as during fasting (Bertil Abrahamsson, Magne Alpsten, Gjorn Bake, Ulf 3onsson, Maria Eriksson-Lepkowska and Annhild Larsson, xe2x80x9cDrug Absorption from nifedipine hydrophilic matrix extended-release (ER) tablet-comparison with an osmotic pump tablet and effect of foodxe2x80x9d, Journal of Controlled Release, 52, pp. 301-310 (1998)). There is no lag time for drug release from hydrophilic matrix ER tablets, and gastric erosion speeds up drug release to an undesirable extent as shown by Abrahamsson, et al.
A discussion of matrix tablet formation and difficulties associated with obtaining the desired drug release rate can be found in U.S. Pat. No. 5,783,212. This patent also points out problems with multilayer matrix tablets containing swellable layers which are not erodible, and erodible layers which are not swellable, including the lack of desired control over drug release rate from hydrophilic matrix gum tablets. U.S. Pat. No. 5,783,212 then describes multiple compression of at least three layers of swellable erodible polymers to form a tablet which controls drug release. U.S. Pat. No. 4,839,177 discloses multiple layer tablets containing a) a deposit-core of active substance, a high degree of swelling polymer and/or a swelling and gelling polymer and b) an aqueous insoluble support platform partially covering the deposit-core. The deposit-core tablet hydrates, swells, and erodes but the aqueous insoluble support platform remains attached to the core tablet for a prolonged time. These hydrophilic gum matrix tablets differ from known hydrophilic gum matrix tablets at least by virtue of their aqueous insoluble support platforms which leave at least one surface exposed and uncoated prior to administration. A particularly good review in this area is xe2x80x9cMulti-layered hydrophilic matrices as constant release devices (Geomatrix Systemsxe2x80x9d, U. Conte, L. Maggi, P. Colombo, and A. La Manna, Journal of Controlled Release, 26 (1993) 39-47.
Conte, et al., identify the advantages of tablets described in U.S. Pat. No. 4,839,177 and point out the need to identify a method for industrial production of the devices described. The key to practicing the ""177 patent is to only partially cover the tablet so there is at all times an uncoated area which allows drug to be released. However, this key feature is impossible to achieve using modem tablet spray coating chambers. Conte, et al., states that xe2x80x9cthe application by casting of an impermeable film on a portion of the matrix tablet could only be obtained manually. To overcome this drawback which does not allow for the automatic production of the system, different approaches were triedxe2x80x9d. That is, the key requirement for practicing the invention of only partially covering the tablet to expose a fixed portion of the tablet results in the impossibility of automatic production by casting or spray coating with impermeable films because such commercial processes cover the entire tablet. Thus, Conte, et al. used a multi-layer compression process known in the art to produce two layer tablets, three layer tablets, or even compression coated tablets which can produce a tablet completely surrounded by an outer compression coat. This process does allow automatic production of multi-layer tablets with characteristics of the ""177 patent, but creates a new problem which is real and significant. That is, multiple layer tablets and compression coating both require special equipment which is very expensive and not widely available. And, such tablets are known to suffer from problems including splitting, cracking, or separation, especially the compression coated tablets. Coats of less than 1 mm are not possible because thinner coats crack at the core tablet edges. This coating thickness requirement can make an already large tablet too large to swallow.
Drug release from hydrophilic gum matrix core tablets partially coated by manual casting of an impermeable film (Conte, et al.) was described by the equation Q/Q=ktn where Q/Q=fraction of drug released at time t, k=kinetic constant, and n=exponent of drug release. When n=1, drug release is zero-order. The n values reported by Conte, et al. were 0.66, 0.64, 0.79, 0.84, and 0.76. Drug release is considered to be approximately zero order when the calculated n value for average dissolution results is greater than at least 0.70. Expected n values associated with drug release from an osmotic pump tablet are closer to 1.0. And, none of the partially covered, hand cast impermeable film coated matrix tablets provided a lag time prior to release of drug. Only the relatively difficult to produce compression coated core tablet was able to provide a lag time prior to drug release. The partially support coated tablets cannot be used for prevention of drug release in the stomach or upper small intestine.
Film coats have been applied to hydrophilic matrix tablets but they are not known to solve the problems described above. An extensive report, for example, presents coating effects on hydroxypropyl methyl cellulose tablets [xe2x80x9cApplication of a Barrier Film Coating to Achieve Zero-Order Release from Hydrophilic Matrix Tabletsxe2x80x9d, R. J. Haluska, D. S. Helms and S. C. Porter, Proceedings of the International Symposium on Release of Bioactive Material, 19 (1992), Controlled Release Society, Inc.; xe2x80x9cApplication of Modified-Release Film Coatings to Hydrophilic Matrix Tablets in Order to Achieve Zero-Order Drug-Release Kineticsxe2x80x9d, Stuart C. Porter, 15th Pharmaceutical Technology Conference, Christchurch College, Oxford, UK, March 19th-21st, (1996)]. A handout entitled xe2x80x9cII. FILM COATING OF HYDROPHILIC MATRICES WITH AQUEOUS POLYMERIC DISPERSIONS: APPLICATION OF OPTIMIZATION TECHNIQUESxe2x80x9d by Davis S. Helms describing these results in detail is available from Colorcon (West Point, Pennsylvania). The following modified Korsmeyer equation was used to describe drug release: M(txe2x88x921)/M(infinity)=k (txe2x88x921)n where M(txe2x88x921)/M(infinity)=fraction of drug released at time t; k=kinetic constant; n=exponent of drug release; and 1=lag time. When n=1, drug release is zero-order. Based on experimentation, linear regression analysis, statistical validity checks, and iterations of the above, the authors teach that the following equations accurately describe drug release from the coated hydrophilic matrix tablets studied. n-value=0.25+6.13 (Surelease amount)xe2x88x925.49 (Opadry(copyright) amount)+2.03 (%HPMC)xe2x88x920.15 ((%HPMCxe2x88x920.125)/0.125)2, and the n value can be higher than 0.9. Lag time=xe2x88x920.3+10.7 (Surelease amount)xe2x88x9221 (Opadry amount)+1.0 (%HPMC)+0.007 (1/(0.101xe2x88x92Surelease amount)). The % drug released after 8 hours=110-335 (Surelease amount)+481 (Opadry amount)xe2x88x92115 (%HPMC)xe2x88x920.031 (1/(0.1005xe2x88x92Surelease amount))xe2x88x920.12 (1/[(%HPMCxe2x88x920.095)/1.095]3). Helms et al. provide information concerning products having 0-25% HPMC. No information, nor predictive value, is provided by such studies at HPMC amounts greater than 25%.
These relationships resulted from observed drug release when the hydrophilic matrix tablet had from 0% to 25% hydroxypropyl methycellulose (HPMC (Methocel K-4M, Dow Chemical)), and the tablets were coated with 0% to 10% weight gain of a coating containing from 0% to 40% of a water soluble, HPMC-based coating formula (Opadry(copyright)YS-1-7006, available commercially from Colorcon, West Point, Pa.) mixed with an aqueous ethycellulose-based dispersion (Surelease(copyright), Colorcon). Surelease(copyright) is an insoluble, barrier coating widely used in coating drug containing tablets or beads to control drug release from the tablets or beads. Polymer-finlmcoated hydrophilic-matrix tablets reported by Helms, et al. have limitations, some of which are discussed below.
For once-a-day dosing of drugs it often is desirable to control drug release for more than 8 hours. Drug release from osmotic pumps often continues for longer than 15 hours, and may continue for 24 hours or longer. To sufficiently prolong drug release from hydrophilic gum matrix tablets in order to meet objectives, it currently is believed desirable to increase the amount of hydrophilic gum to over 30%, and more than 40% often is desirable. With only 25% HPMC in the core tablet, Helms, et al. report that increased modifier levels in the coating causes barrier coat failure, which results in no significant change in n-value or release profile when compared to uncoated standard. Barrier coat failure is undesirable. Barrier coat failure also occurs with coating weight gains below 4% as there is insufficient film coat strength to resist the swelling of the hydrophilic substrate. The situation is worse with 40% or more hydrophilic gum in the core tablet because swelling increases with increased hydrophilic gum.
It is known by those skilled in the art of tablet coating that barrier coat failure reported by Helms, et al., which results in no significant change in n-value or release profile when compared to uncoated standard, is unacceptable. Increasing barrier film coat thickness is the approach used to prevent barrier coat failure. But, Helms et al. also report that one potential undesirable effect of increasing barrier film coat thickness is that high levels of unmodified barrier coat can lead to unacceptably long lag times or even drug release xe2x80x9cshut downxe2x80x9d where the barrier coating becomes completely impermeable. Increasing modifier levels in the barrier coating helps prevent the barrier coat from being completely impermeable, but then barrier coat failure occurs.
Many hydrophilic gums swell more extensively than HPMC K-4M (Wattanaporn Tavipatana, xe2x80x9cBioadhesive Polymers in Drug Product Formulationsxe2x80x9d, Doctor of Philosophy Thesis, Oregon State University, 1988). These other polymers can provide desired results in a hydrophilic matrix gum polymer tablet, but their extensive swelling results in increased failure of the barrier coat. Some non-limiting examples of such polymers include polycarbophil, polyethylene oxide, xanthan gum, sodium carbopol, and carboxymethyl cellulose. Some of these gums expand much more in intestinal fluid than in gastric fluid, e.g., xanthan gum, sodium carbopol, and polyethylene oxide 5,000,000. Triple layer compression of such tablets, or manually applying an impermeable film on a portion of the matrix tablet, could be used to modify and improve drug release patterns as taught by Conte, et al. But spray coating tablets having these extensively swelling materials is taught by Helms, et al., to result in barrier coat failure. If enough coating is applied to prevent barrier coat failure, then unacceptably long lag times or even drug release shut down occurs. Helms et al. is silent about the use and effect of mixtures of materials.
Even if HPMC is the hydrophilic polymer matrix gum in a core tablet, as the amount of equations of Helms, et al., above). This means that the release rate becomes less and less like zero order, i.e., goes away from the desired drug release pattern. Further, the expected drug release pattern according to Helms, et al., with more than 30-40% hydrophilic gum in the tablet, is such that the equations clearly show too much burst effect and overall the release of drug is incomplete in 24 hours, which means that less than the total amount of drug can be absorbed in the body. See, for example, FIG. 1 which is generated with the equations of Helms for various amounts of Surelease(copyright) rate controlling membrane containing 20% Opadry(copyright) modifier. Thus, it is desirable to increase the amount of hydrophilic gum to over 30%, and often to more than 40% to extend drug release to allow for once-a-day dosing, Helms teaches that drug release patterns from such formulations are undesirable.
Tablets containing high amounts of a hydrophilic gum are reported by Kim and Fasshi to achieve desirable zero-order drug release but these tablets do not achieve other desired objectives. Kim and Fasshi report preparation of tablets containing about 750%-90% hydrophilic gum materials. Each tablet was prepared one-at-a-time by weighing the necessary amount of powders, hand filling into a die, and compressing into tablets using a carver press. Using this common laboratory method, tablets prepared by combining HPMC and highly methoxylated pectin with drugs can provide nearly zero-order drug release in the USP dissolution apparatus, paddle stirring at 50 RPM (Hyunjo Kim and Reza Fasshi, Application of a Binary Polymer System in Drug Release Rate Modulation. 1. Characterization of Release Mechanism, Journal of Pharmaceutical Sciences, Vol. 86, No.3, pp. 316-322, 1997; Hyunjo Kim and Reza Fasshi, Application of a Binary Polymer System in Drug Release Rate Modulation. 2. Influence of Formulation Variables and Hydrodynamic Conditions on Release Kinetics, Journal of Pharmaceutical Sciences, Vol. 86, No.3, pp.323-328, 1997; Hyunjo Kim and Reza Fasshi, A New Terinary Polymer Matrix System for Controlled Drug Delivery of Highly Soluble Drugs; I. Diltiazem Hydrochloride, Pharmaceutical Research, Vol. 14, pp. 1415-1421, 1997). These tablets exhibit no lag time and are sensitive to administration with food as taught by Abrahamsson, et al.
Highly methoxylated pectin was used by Kim and Fasshi because low methoxylated pectin is an anionic polysaccharide, and gelation of low methoxylated pectin is expected to be undesirably influenced by changes in gastrointestinal pH, which also would modify drug release rate. Pectin is the methylated ester of polygalacturonic acid, and typically is commercially extracted from citrus peels and apple pomace under mildly acidic conditions. A typical pectin molecule includes plural molecules of galacturonic acid connected in a linear chain, typically 300 to 1000 such molecules in a typical pectin molecule. The acid can be the free acid, or it can be an ester, such as a methyl ester, which is referred to as methoxylation, and different degrees of methoxylation can occur. For example, if 3 out of every 5 galacturonic acids are methoxylated, this then represents a degree of methoxylation of 3 out of 5, or 60 percent. xe2x80x9cDMxe2x80x9d or xe2x80x9cDExe2x80x9d is short for degree of esterification. Both terms are interchangeable, and they refer to the percentage of acid groups which are present in the pectin molecule as the methyl ester. Any pectin which has a DE of 50% or more is referred to as high methoxy, or highly methoxylated, pectin, and any pectin which as a DE of less than 50% is referred to as low methoxy, or low methoxylated, pectin.
Highly methoxylated pectin gelation is not affected by such pH changes. Low methoxylated pectin reportedly requires the presence of calcium ions to gel. Gelation of pectin with calcium to produce small spheres designed for delivering drug into the colon has been described (U.S. Pat. No. 5,505,966). Other examples of required cross-linking agents in gums to control drug delivery exist. U.S. Pat. No. 5,455,046 describes matrix tablets composed of heteropolysaccharide gums and a homopolysaccharaide gum capable of cross-linking the heteropotysaccharide gum, plus a cationic cross-linking agent, such as calcium chloride, for sustained release of a medicament with a solubility of less than about 10 g/L. These cationic cross-linked gums may, in addition, also contain other acceptable gelling agents including vegetable gums, such as alginates, carrageenan, pectin, guar gum, xanthan gum, modified starch, hydroxypropyl methyl cellulose, and other cellulosic materials, so long as there is homopolysaccharaide gum capable of cross-linking said heteropolysaccharide gum plus a cationic cross-linking agent. The requirement for cross-linking often is undesirable because the reaction or agent may adversely affect drug stability or release.
Tablets described by U.S. Pat. No. 5,455,046 containing 50% xanthan gum/locust bean gum cross-linked with calcium (Compactrol) when coated to 5% weight gain of hydrophobic polymer (Surelease(copyright)) release drug consistent with no lag time and essentially no coating effect. The inventors state that the coated tablet xe2x80x9cappears to be an acceptable 24 hour formulation. However, the results obtained indicate that acceptable 24-hour release formulations may be obtained with or without the hydrophobic coatingxe2x80x9d in cross-linked gums, meaning that the coating is not producing a lag time. Table 16 from this patent is reproduced below.
Many hydrophilic gum materials, including those used by Kim and Fasshi do not flow well in conventional tablet machine hoppers, and do not fill well into tablet dies. Tablet making experiments have shown that mixtures of HPMC and pectin powders sufficient to make up 95% of a 450 mg tablet did not flow well in commercial tablet machines and block or xe2x80x9cbridgexe2x80x9d in the hopper. Good tablets could not be made at very high speeds. It was necessary to utilize vibration-aided flow and reduced speeds. These tablets could be produced on a relatively small and slow scale for testing, but the formulation was not well suited for mass production. While these powders could be diluted with flow aids such as microcrystalline cellulose or fast flow lactose to produce a mixture suitable for compression on commercial tablet machines, the teachings of Kim and Fasshi show that such formulations have a drug release burst and are no longer linear while releasing drug, and drug is released over a shorter time when water-soluble additives are included in the formulation.
In summary, a need remains for a controlled-release tablet formulation which is relatively easy and inexpensive to produce using standard equipment, and which can easily be modified by the formulator to program drug release as desired. For hydrophilic matrix tablets, too little hydrophilic gum in the tablet results in drug release which is too fast overall, and too much hydrophilic gum results in too little drug release in a reasonable time. Coating on these tablets must be sufficiently thick and strong to prevent barrier coat failure, and still does not give the desired drug release. It has now been unexpectedly discovered that all of the above described problems can be easily overcome in preparation of suitable controlled release tablets.
This invention concerns an expanding tablet to which coating has been applied to all exposed surfaces by spraying with a drug release controlling membrane material and, after swallowing, the tablet hydrates and expands such that the membrane ruptures mostly in only one direction to directly expose some surfaces of the core tablet to hydrating and eroding liquids, thus generating in situ a tablet which is platform supported on non-exposed surfaces, and which releases active ingredient in approximately zero order fashion. More particularly, the dosage form is adapted for controlled release of various pharmaceuticals.
Working embodiments of tablets according to the present invention comprise at least one expanding material, or a mixture of expanding materials, such as a hydrophilic polymer gum or mixture of hydrophilic polymer gums, in a matrix tablet which has been polymer film coated over the entire surface. Such tablets unexpectedly control drug release better than as described in U.S. Pat. No. 4,839,177 (Geomatrix tablet). There is no need to only partially cover the tablet, which means that application of an impermeable film on only a portion of the matrix tablet is no longer required to obtain the desired drug release. Thus, unlike U.S. Pat. No. 4,839,177, the present invention allows for automatic production. Manufacture is greatly simplified because standard equipment can be used and the core tablet can be coated over the entire surface in a standard tablet coating chamber. Relatively high amounts of hydrophilic gum matrix can be used and the time required to complete drug release can be controlled to occur over 24 hours, or faster if desired.
Importantly, drug release can be essentially equivalent to drug release from the more complex osmotic pump system, if desired. Embodiments of tablets according to the present invention can have a lag time like an osmotic pump tablet if desired, and release of drug occurs in a desired controlled release fashion. In some cases drug bioavailability is expected to he increased relative to drug bioavailability from an osmotic pump tablet In one embodiment, a programmed release of drug is obtained by coating a tablet with additional drug either within the film coat or over the film coat, or in both places as needed to obtain a desired drug release profile. In this case, there may not be a lag time from the final tablet as drug release from the outer layer(s) may be so fast as to produce an immediate burst effect if desired, or the release may be sufficiently slow and short that the total release from the outer layer(s) in combination with delayed release from the film coated interior will be nearly zero-order beginning at time zero, or after a desired time.
A working embodiment of the tablet was a spray-coated tablet comprising a core having greater than 25% of an expandable material which expands upon exposure to an aqueous environment and at least one active ingredient, e.g., glipizide, and an outer rupturable coating surrounding the core comprising a rate release modifying membrane and a water-soluble modifier. The tablet also can include additional coating layers, such as an over coating of an active ingredient, or the rate release modifying membrane may be over coated or undercoated with an enteric coating material. The tablet can include a mixture of hydrophilic gum polymers, at least one of which is modified by enzymes in the intestinal tract, such as pectin or guar gum. Furthermore, the rate release modifying membrane may contain one or more active ingredients. Examples, without limitation, of rate release modifying membranes include ethyl cellulose or a methacrylate polymer containing modifiers, which influence active ingredient release.
Typically, the tablet includes a belly band, and at least a portion of the coating ruptures adjacent to or in the xe2x80x9cbelly bandxe2x80x9d area of the tablet upon exposure to an aqueous fluid, but the coating remains attached to some tablet surfaces as shown in the drawings. This produces a support platform in situ for drug delivery. Working embodiments of the tablets had belly bands between 1 and 8 mm thick and where the length of the tablet was at least 8 mm. Moreover, the belly band in initial embodiments typically was less than a vertical height of the tablet as measured at a center portion of the tablet.
Tablets according to the invention can be designed to have a drug-delivery lag time of from about 0.5 hours or more and less than or equal to about 6 hours. Preferably, the lag time is from about 1 to about 3 hours. Such tablets also can be designed to sustain release of an active ingredient following a lag time sufficient to provide therapeutically effective active ingredient concentrations when administered in a once- or twice-daily dosing regimen. Dissolution of an active ingredient from such tablets measured in vitro in a USP paddle stirring apparatus in appropriate aqueous media at 37xc2x0 C., can substantially correspond to the following: from 0 to 5% of the total active ingredient is released after one hour; from 0 to 40% of the total active ingredient is released after four hours; from 20 to 80% of the total active ingredient is released after eight hours; and not less than 80% of the total active ingredient is released in 24 hours.
The n value for such tablets typically is 0.7 or more from time of 10% active ingredient released until time of 75% active ingredient released, and preferably the n value is 0.85 or more from time of 10% active ingredient released until time of 85% active ingredient released.
Another embodiment of the tablet comprised one or more active ingredients, a mixture of hydrophilic gum polymers where the mixture comprises between about 40% and 85% by dry weight of the tablet ingredients, the mixture comprising at least one hydrophilic gum polymer which is modified by enzymes in the intestinal tract, such as pectin and/or guar gum, at least one excipient which promotes powder mixture flow, and a spray coating over the external surface of the tablet, the coating comprising a rate release controlling membrane.
Still another embodiment of the invention comprised a spray-coated tablet which exhibits a lag time for active ingredient dissolution. The tablet comprised glipizide, a mixture of hydrophilic gum polymers comprising at least one hydrophilic gum polymer which is modified by enzymes in the intestinal tract, and a rate release controlling membrane overcoating the mixture. For such tablets, at least one hydrophilic gum was hydroxypropyl methyl cellulose, the hydrophilic gum polymer which is modified by enzymes in the intestinal tract was pectin, and the rate controlling membrane comprised ethyl cellulose or a methacrylate. For such tablets having a first rate controlling membrane, the first rate controlling membrane may have been over coated with a second membrane. The second membrane could be added for a number of reasons, including aesthetic purposes, rate controlling purposes, enteric controlling purposes, or to add additional drug to the tablet. Moreover, the rate controlling membrane may have been over coated with one or more active ingredients which may be the same or different from the active ingredients in the core tablet, and release of the active ingredient may or may not have exhibited a lag time for active ingredient dissolution.
Still another embodiment of the tablet which exhibited a lag time for active ingredient dissolution comprised one or more active ingredients, a mixture of hydrophilic gum polymers comprising between about 40% and about 85% by dry weight of all tablet ingredients, the mixture comprising at least one hydrophilic gum polymer which is modified by enzymes in the intestinal tract and at least one excipient which promotes powder mixture flow and attracts water, and an outer rupturable coating comprising a rate release controlling membrane.
Still another embodiment of the invention comprised a barrier coated tablet which generates a support platform in situ. A drug dissolution versus time curve for such tablet indicated a lag time of between 1 and 3 hours, an n value of 0.85 or greater, and a k value between 0.04 and 0.25.
Still another embodiment of the invention comprised a barrier coated tablet which generates a support platform in situ, and a drug dissolution versus time curve with a lag time of between 1 and 3 hours, an n value of 0.85 or greater, and a k value between 0.05 and 0.1.
Still another embodiment of the invention comprised a core comprising an active ingredient, an enzymatically modifiable, expandable material which expands upon exposure to an aqueous environment, and an outer rupturable rate release modifying membrane, the tablet providing active ingredient release over at least a 16-hour period.
Still another embodiment of the invention concerns a tablet having a drug-delivery lag time having a core comprising an active ingredient, a water-soluble modifier gum, and at least one second expandable gum which expands upon exposure to an aqueous environment, and an outer rupturable rate release modifying membrane over coating the core.
The present invention also provides a method for administering an active ingredient. The method comprises (1) providing a tablet comprising a core having an active ingredient and an expandable material which expands upon exposure to aqueous environment, the core surrounded by an outer rate release modifying membrane which ruptures upon exposure to aqueous environment, and (2) administering the tablet to a patient.